This invention relates to substituted 5-cyano-2-aminopyrimidines, to processes for their preparation, to pharmaceutical compositions containing them, and to their use in medicine.
Angiogenesis, the growth of capillaries from existing blood vessels, is an essential process in normal embryonic development, tissue repair and some aspects of female reproductive function. It is also associated with the development of several pathological disorders including solid tumour growth, metastasis, psoriasis and rheumatoid arthritis, as well as diabetic retinopathy and age related macular degeneration [Folkman, Nature Medicine, (1995) 1, 27-310].
Several growth factors have been shown to mediate angiogenesis through alteration of vascular permeability, including vascular endothelial growth factor [VEGF; G. Breier et al., Trends in Cell Biology, (1996), 6, 454-6], platelet derived growth factor (PDGF) and acidic and basic fibroblast growth factors (a and b FGF).
VEGF in dimeric form is a ligand that binds to two transmembrane tyrosine kinase associated receptors, expressed exclusively on proliferating endothelial cells, KDR (Flk-1 in mice) also known as VEGFR-2, and Flt-1 also known as VEGFR-1. Binding of VEGF to KDR/Flk and Fit leads to receptor dimerisation, kinase activation, autophosphorylation of the receptor and phosphorylation of intracellular substrates. An analogous series of events ensues after ligand occupancy of the more widely expressed tyrosine kinase associated FGFr receptor by aFGF or bFGF. Thus receptor tyrosine kinase activity initiates a cellular signalling pathway leading to proliferation.
Antagonism of VEGF with antibody completely suppresses neovascularisation and growth of human rhabdomyosarcoma A673 speroids in athymic mice [Borgstrom et al, Cancer Res., (1996), 56 4032-4039]. Suppression of bFGF gene expression by interferons a and b inhibits capillary density in mice, leading to pancreatic eyelet tumour suppression [Folkman et al, Proc. Natl. Acad.Sci. (1996), 93, 2002 and Singh et al Proc.Natl. Acad. Sci. (1995), 92, 10457). Other receptor associated kinases such as PDGF and EGFr may also have some role in mediating angiogenesis.
We have now found a series of substituted 5-cyano-2-aminopyrimidines which are potent and selective inhibitors of receptor tyrosine kinases involved in angiogenesis, especially KDR kinase and/or FGFr kinase. Selective inhibition of these kinases can be expected to have a beneficial effect and the compounds are thus of use in the prophylaxis and treatment of disease states associated with angiogenesis, as described hereinafter.
Thus, according to one aspect of the invention, we provide a compound of formula (1): 
wherein
Ar is an optionally substituted aromatic or heteroaromatic group;
R1 is a hydrogen atom or a straight or branched chain alkyl group;
R2 is a xe2x80x94X1xe2x80x94R3 group where X1 is a direct bond or a linker atom or group, and
R3 is an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group; and the salts, solvates, hydrates and N-oxides thereof.
When Ar in the compounds of formula (1) is an aromatic group it may be for example an optionally substituted monocyclic or bicyclic fused ring C6-12aromatic group, such as an optionally substituted phenyl, 1- or 2-naphthyl, 1- or 2-tetrahydronaphthyl, indanyl or indenyl group.
When the group Ar in compounds of the invention is a heteroaromatic group it may be an optionally substituted C1-13 heteroaromatic group, such as a C1-9 heteroaromatic group, containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
In general, the heteroaromatic group may be for example an optionally substituted monocyclic heteroaromatic, or a bicyclic or tricyclic fused-ring heteroaromatic group. Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Bicyclic heteroaromatic groups include for example nine- to thirteen-membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms. Tricyclic heteroaromatic groups include for example ten- to fourteen-membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms. The heteroaromatic group may be attached to the remainder of the compound of formula (1) through any of its ring carbon atoms.
Particular examples of heteroaromatic groups represented by Ar include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, 1,2,5-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, indazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydro-quinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.
Optional substituents which may be present on the aromatic or heteroaromatic groups represented by Ar include one, two, three or more substituents, each represented by an atom or group xe2x80x94R4 or -Alk(R4)m, where R4 is a halogen atom, or an amino (xe2x80x94NH2), substituted amino, nitro, cyano, hydroxyl (xe2x80x94OH), substituted hydroxyl, formyl, carboxyl (xe2x80x94CO2H), esterified carboxyl, thiol (xe2x80x94SH), substituted thiol, xe2x80x94COR5 [where R5 is a -Alk(R4)m, aryl or heteroaryl group], xe2x80x94CSR5, xe2x80x94SO3H, xe2x80x94S2R5, xe2x80x94SO2NH2, xe2x80x94SO2NHR5, xe2x80x94SO2N[R5]2, xe2x80x94CONH2, xe2x80x94CSNH2, xe2x80x94CONHR5, xe2x80x94CSNHR5, xe2x80x94CON[R5]2, xe2x80x94CSN[R5]2, xe2x80x94NHSO2H, xe2x80x94NHSO2R5, xe2x80x94N[SO2R5]2, xe2x80x94NHSO2NH2, xe2x80x94NHSO2NHR5,
xe2x80x94NHSO2N[R5]2, xe2x80x94NHCOR5, xe2x80x94NHCONH2, xe2x80x94NHCONHR5, xe2x80x94NHCON[R5]2, xe2x80x94NHCSR5, xe2x80x94NHC(O)OR5, or optionally substituted cycloaliphatic, heteroycloaliphatic, aryl or heteroaryl group; Alk is a straight or branched C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene chain, optionally interrupted by one, two or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms atoms or groups selected from xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94 or xe2x80x94N(R6)xe2x80x94 [where R6 is a hydrogen atom or a straight or branched chain C1-6 alkyl group]; and m is zero or an integer 1, 2 or 3.
When in the group -Alk(R4)m m is an integer 1, 2 or 3, it is to be understood that the substituent or substituents R4 may be present on any suitable carbon atom in -Alk. Where more than one R4 substituent is present these may be the same or different and may be present on the same or different atom in -Alk or in R4 as appropriate. Thus for example, -Alk(R4)m may represent a xe2x80x94CH(R4)2 group, such as a xe2x80x94CH(OH)Ar1 group where Ar1 is an aryl or heteroaryl group as defined below. Clearly, when m is zero and no substituent R4 is present the alkylene, alkenylene or alkynylene chain represented by Alk becomes an alkyl, alkenyl or alkynyl group.
When R4 is a substituted amino group it may be for example a group xe2x80x94NHR5 [where R5 is as defined above] or a group xe2x80x94N[R5]2 wherein each R5 group is the same or different.
When R4 is a halogen atom it may be for example a fluorine, chlorine, bromine, or iodine atom.
When R4 is a substituted hydroxyl or substituted thiol group it may be for example a group xe2x80x94OR5 or xe2x80x94SR5 respectively.
Esterified carboxyl groups represented by the group R4 include groups of formula xe2x80x94CO2Alk1 wherein Alk1 is a straight or branched, optionally substituted C1-8 alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; a C6-12arylC1-8alkyl group such as an optionally substituted benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; a C6-12aryl group such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl group; a C6-12 aryloxyC1-8alkyl group such as an optionally substituted phenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl, or 2-naphthyloxymethyl group; an optionally substituted C1-8alkanoyloxyC1-8alkyl group, such as a pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl group; or a C6-12 aroyloxyC1-8alkyl group such as an optionally substituted benzoyloxyethyl or benzoyl-oxypropyl group. Optional substituents present on the Alk1 group include R4 substituents described above.
When Alk is present in or as a substituent, it may be for example a methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, atoms or xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94 or xe2x80x94N(R6)xe2x80x94 (where R6 is a hydrogen atom or a straight or branched C1-6alkyl group) groups.
When R4is present in compounds of formula (1) as an optionally substituted cycloaliphatic group it may be an optionally substituted C3-10 cycloaliphatic group. Particular examples include optionally substituted C3-10cycloalkyl, e.g. C3-7cycloalkyl, or C3-10cycloalkenyl e.g. C3-7cyclo-alkenyl groups.
Heterocycloaliphatic groups represented by R4 include the aliphatic or cycloaliphatic groups just described for R4 but with each group additionally containing one, two, three or four heteroatoms or heteroatom-containing groups selected from xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R6)xe2x80x94, xe2x80x94C(O), xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O2)xe2x80x94 groups.
Particular examples of R4 cycloaliphatic and heterocycloaliphatic groups include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2,4-cyclopentadien-1-yl, 3,5,-cyclohexadien-1-yl, tetrahydrofuranyl, pyrroline, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, dioxolanyl, e.g. 1,3-dioxolanyl, imidazolinyl, e.g. 2-imidazolinyl, imidazolidinyl, pyrazolinyl, e.g. 2-pyrazolinyl, pyrazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-trithianyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-, 6H-1,2-, 2H-1,2- or 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, isoxazinyl, oxathiazinyl, e.g. 1,2,5 or 1,2,6-oxathiazinyl, or 1,3,5-oxadiazinyl groups.
Optional substituents which may be present on R4 cycloaliphatic and heterocycloaliphatic groups include one, two, three or more substituents selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or hydroxyl, C1-6alkoxy , e.g. methoxy or ethoxy, thiol, C1-6alkylthio, e.g. methylthio or ethylthio, hydroxy, C1-6alkyl, e.g. hydroxymethyl, hydroxyethyl, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NHR5 or xe2x80x94N(R5)2 groups.
Aryl and heteroaryl groups represented by the groups R4, R5 or Ar1 include for example optionally substituted monocyclic or bicyclic C6-12 aromatic groups, e.g. phenyl groups, or C1-9 heteroaromatic groups such as those described above in relation to the group Ar. Optional substituents which may be present on these groups include one, two or three R4a atoms or groups described below.
Particularly useful atoms or groups represented by R4, -Alk(R4)m or R4a as appropriate include fluorine, chlorine, bromine or iodine atoms, or C1-6alkyl, e.g. methyl or ethyl, C1-6alkylamino, e.g. methylamino or ethylamino, hydroxyC1-6alkyl, e.g. hydroxymethyl or hydroxyethyl, hydroxyC2-6alkoxy, e.g. 2-hydroxyethoxy or 3-hydroxyethoxy, C1-6alkylthiol e.g. methylthiol or ethylthiol, C1-6alkoxy, e.g. methoxy or ethoxy, C5-7cycloalkoxy, e.g. cyclopentyloxy, haloC1-6alkyl, e.g. trifluoromethyl, amino (xe2x80x94NH2), aminoC1-6alkyl, e.g. aminomethyl or aminoethyl, C1-6dialkylamino, e.g. dimethylamino or diethylamino, aminoC1-6alkoxy, C1-6alkylaminoC1-6alkoxy, diC1-6alkylaminoC1-6alkoxy, imido, such as phthalimido or naphthalimido, e.g. 1,8-naphthalimido, 1,1,3-trioxobenzo[d]thiazolidino, nitro, cyano, hydroxyl (xe2x80x94OH), formyl [HC(O)xe2x80x94], carboxyl (xe2x80x94CO2H), xe2x80x94CO2Alk1 [where Alk1 is as defined above], C1-6 alkanoyl e.g. acetyl, thiol (xe2x80x94SH), thioC1-6alkyl, e.g. thiomethyl or thioethyl, xe2x80x94SC(NH2+)NH2, sulphonyl (xe2x80x94SO3H), C1-6alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl (xe2x80x94SO2NH2), C1-6alkylaminosulphonyl, e.g. methylaminosulphonyl or ethylaminosulphonyl, C1-6dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl, carboxamido (xe2x80x94CONH2), C1-6alkylaminocarbonyl, e.g. methylaminocarbonyl or ethylaminocarbonyl, C1-6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or diethylaminocarbonyl, sulphonylamino (xe2x80x94NHSO2H), C1-6alkylsulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, C1-6dialkylsulphonylamino, e.g. dimethylsulphonylamino or diethylsulphonylamino, optionally substituted phenylsulphonylamino, e.g. 2-, 3- or 4-substituted phenylsulphonylamino such as 2-nitrophenylsulphonylamino, aminosulphonylamino (xe2x80x94NHSO2NH2), C1-6alkylaminosulphonylamino, e.g. methylaminosulphonylamino or ethylaminosulphonylamino, C1-6dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, phenylaminosulphonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino e.g. methylaminocarbonylamino or ethylaminocarbonylamino, C1-6dialkylaminocarbonylamino, e.g. dimethylaminocarbonylamino or diethylaminocarbonylamino, phenylaminocarbonylamino, C1-6alkanoylamino, e.g. acetylamino, optionally substituted phenylcarbonylamino, C1-6alkanoylaminoC1-6alkyl, e.g. acetylaminomethyl, C1-6alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino, optionally substituted heteroC3-6cycloalkyl, e.g. piperidinyl, piperazinyl, 4-(C1-6alkyl)piperazinyl, e.g. 4-methylpiperazinyl, homopipeprazinyl, or morpholinyl, optionally substituted heteroC3-6cycloalkylC1-6alkyl, e.g. piperidinylC1-6alkyl, piperazinylC1-6alkyl, 4-(C1-6alkyl)piperazinylC1-6alkyl, e.g. 4-methylpiperazinylmethyl, or morpholinylC1-6alkyl, optionally substituted heteroC3-6cycloalkylC1-6alkoxy, e.g. morpholinylC1-6alkoxy, optionally substituted heteroC3-6alkylC1-6alkylamino, optionally substituted heteroC3-6cycloalkylamino, tetrazolyl, optionally substituted imidazolyl, optionally substituted triazolyl, e.g.1,2,4-, 1,2,3-, 1,3,4- or 1,2,5-triazolyl, optionally substituted imidazolylC1-6alkyl, optionally substituted imidazolylC1-6alkoxy, optionally substituted triazolylC1-6alkoxy, optionally substituted imidazolylaminoC1-6alkoxy, optionally substituted phenylamino, optionally substituted benzylamino, optionally substituted benzyloxy, or optionally substituted pyridylmethylamino group.
Where desired, two R4 or -Alk(R4)m substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C2-6alkylenedioxy group such as ethylenedioxy.
It will be appreciated that where two or more R4, -Alk(R4)m or R4a substituents are present, these need not necessarily be the same atoms and/or groups.
Especially useful R4, -Alk(R4)m or R4a substituents include for example fluorine, chlorine, bromine or iodine atoms, or a methylamino, ethylamino, hydroxymethyl, hydroxyethyl, methylthiol, ethylthiol, methoxy, ethoxy, n-propoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutoxy, 2-aminoethoxy, 3-aminopropoxy, 2-(methylamino)ethoxy, 2-(dimethylamino)ethoxy, 3-(dimethyl-amino)propoxy, cyclopentyloxy, cyclohexyl, cyclohexylamino, 2-hydroxycyclohexylamino, trifluoromethyl, trifluoromethoxy, methylamino, ethylamino, amino (xe2x80x94NH)2, aminomethyl, aminoethyl, dimethylamino, diethylamino, ethyl(methyl)amino, propyl(methyl)amino, 2-hydroxyethylamino, 3-hydroxypropylamino, 4-hydroxybutylamino, 2-aminoethylamino, 3-aminopropylamino, 4-aminobutylamino, 2-(methylamino)ethylamino, 2-(ethylamino)ethylamino, 2-(i-propylamino)ethylamino, 3-(i-propylamino)propylamino, 2-(dimethylamino)ethylamino, 3-(dimethylamino)propylamino, 2-(diethylamino)ethylamino, 3-(diethylamino)propylamino, 2-(methylamino)ethyl(methyl)amino, 3-(methylamino)propyl(methyl)amino, 2-(dimethylamino)ethyl(methyl)amino, 2-(dimethylamino)ethyl(ethyl)amino, dimethylaminoethoxy, nitro, cyano, hydroxyl (xe2x80x94OH), formyl [HC(O)xe2x80x94], carboxyl (xe2x80x94CO2H), xe2x80x94CH2CO2H, xe2x80x94OCH2CO2H, xe2x80x94CO2CH3, xe2x80x94CO2CH2CH3, xe2x80x94CH2CO2CH3, xe2x80x94CH2CO2CH2CH3, xe2x80x94CH2CO2CH2phenyl, t-butoxycarbonylmethoxy, acetyl, phenacetyl thio (xe2x80x94SH), thiomethyl, thioethyl, xe2x80x94SC(NH)NH2, sulphonyl (xe2x80x94SO2H), methylsulphonyl, methylaminosulphonyl, ethylaminosulphonyl, dimethylaminosulphonyl, diethylaminosulphonyl, carboxamido (xe2x80x94CONH2), methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylaminocarbonylmethyl, xe2x80x94NHC(S)NH2, sulphonylamino (xe2x80x94NHSO2H), methylsulphonylamino ethylsulphonylamino, dimethylsulphonylamino, diethylsulphonylamino, sulphonylamino (xe2x80x94NHSO2NH2), methylaminosulphonylamino, ethylaminosulphonylamino, dimethylaminosulphonylamino, diethylaminosulphonylamino, methylaminocarbonylamino, ethylaminocarbonylamino, dimethylaminocarbonylamino diethylaminocarbonylamino, acetylamino, phenylcarbonylamino, aminomethylcarbonylamino, acetylaminomethyl, methoxycarbonylamino, ethoxycarbonylamino, t-butoxycarbonylamino, pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, 4-methylpiperazinylC1-6alkylphenylcarbonylamino, homopiperazinyl, morpholinyl, pyrrolidinylC1-6alkyl, piperidinylC1-6alkyl, piperazinylC1-6alkyl, 4-(C1-6alkyl)piperazinylC1-6alkyl, morpholinylC1-6alkyl, morpholinoethoxy, 2-pyrrolidinylethylamino, 2-(1-methylpyrrolidinyl)ethylamino, 1-ethylpyrrolidinylmethylamino, piperidinylamino, 1-benzylpiperidinylamino, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1,2,5-triazolyl, C1-6alkylimidazolylC1-6alkyl, imidazolylC1-6alkoxy, triazolylC1-6alkyl, triazolylC1-6alkoxy, imidazolylC1-6alkyl such as imidazlylmethyl or imidazolylethyl, 4-(methoxy)phenylamino, 4-(3-hydroxypropyl)phenylamino, benzylamino, benzyloxy or pyridiylmethylamino group.
In the compounds of formula (1), when the group R1 or the group R6 [when present as xe2x80x94N(R6)xe2x80x94] is a straight or branched chain alkyl group it may be for example a C1-6 straight or branched chain alkyl group such as a methyl, ethyl, n-propyl or isopropyl group.
Linker atoms represented by X1 when present in compounds of formula (1) include xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms. When X1 is a linker group it may be for example a xe2x80x94C(O)xe2x80x94,xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2, xe2x80x94N(R)7)xe2x80x94 [where R7 is a hydrogen atom or a C1-6 alkyl, e.g. methyl or ethyl, group], xe2x80x94C(R7)2xe2x80x94, xe2x80x94CON(R7)xe2x80x94, xe2x80x94OC(O)N(R7)xe2x80x94, xe2x80x94CSN(R7)xe2x80x94, xe2x80x94N(R7)COxe2x80x94, xe2x80x94N(R7)C(O)Oxe2x80x94, xe2x80x94N(R7)CSxe2x80x94, xe2x80x94SON(R7), xe2x80x94SO2N(R7), xe2x80x94N(R7)SO2xe2x80x94, xe2x80x94N(R7)CON(R7)xe2x80x94, xe2x80x94N(R7)CSN(R7)xe2x80x94, xe2x80x94N(R7)SON(R7)xe2x80x94 or xe2x80x94N(R7)SO2N(R7) group.
In the compounds of formula (1), when R2 is xe2x80x94X1R3 and R3 is an optionally substituted aliphatic group, R3 may be an optionally substituted C1-10 aliphatic group for example an optionally substituted straight or branched chain C1-6 alkyl, e.g. C1-3 alkyl, C2-6 alkenyl, e.g. C2-4 alkenyl, or C2-6 alkynyl, e.g. C2-4 alkynyl group. Each of said groups may be optionally interrupted by one or two heteroatoms or heteroatom-containing groups represented by X2 [where X2 is an atom or group as just described for X1], to form an optionally substituted R3 heteroaliphatic group.
Particular examples of aliphatic groups represented by R3 include optionally substituted xe2x80x94CH3, xe2x80x94CH2CH3 xe2x80x94(CH2)2CH3, xe2x80x94CH(CH3)2, xe2x80x94C(CH3)3, xe2x80x94(CH2)3CH3, xe2x80x94CH(CH3)CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94C(CH3)3, xe2x80x94(CH2)4CH3, xe2x80x94(CH2)5CH3, xe2x80x94CHCH2, xe2x80x94CHCHCH3, xe2x80x94CH2CHCH2, xe2x80x94CHCHCH2CH3, xe2x80x94CH2CHCHCH3, xe2x80x94(CH2)2CHCH2, xe2x80x94CCH, xe2x80x94CCCH3, xe2x80x94CH2CCH, xe2x80x94CCCH2CH3, xe2x80x94CH2CCCH3, or xe2x80x94(CH2)2CCH groups. Where appropriate each of said groups may be optionally interrupted by one or two atoms and/or groups X2 to form an optionally substituted heteroaliphatic group. Particular examples include xe2x80x94CH2X2CH3, xe2x80x94CH2X2CH2CH3, xe2x80x94(CH2)2X2CH3 and xe2x80x94(CH2)2X2CH2CH3 groups.
The optional substituents which may be present on these aliphatic and/or heteroaliphatic groups include one, two, three or more substituents selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or hydroxyl, C1-6 alkoxy, e.g. methoxy or ethoxy, thiol, C1-6 alkylthio, e.g. methylthio or ethylthio, xe2x80x94SC(NH)NH2, xe2x80x94CH2C(NH)NH2, amino, substituted amino or cyclic amino groups.
Substituted amino groups include for example groups of formulae xe2x80x94NR8R9 [where R8 is an optionally substituted C1-6alkyl, C2-6alkenyl or C2-6alkynyl group optionally interrupted by one or two heteroatoms or heteroatom-containing groups represented by X3 (where X3 is an atom or group as described above for X1) and R9 is a hydrogen atom or is a group as just defined for R8], xe2x80x94N(R9)COR8, xe2x80x94N(R9)CSR8, xe2x80x94N(R9)SOR8, xe2x80x94N(R9)SO2R8, xe2x80x94N(R9)CONH2, xe2x80x94N(R9)CONR8R9, xe2x80x94N(R9)C(O)OR8, xe2x80x94N(R9)C(NH)NH2, xe2x80x94N(R9)C(N H)NR8NR9, xe2x80x94N(R9)CSNH2, xe2x80x94N(R9)CSNR8R9, xe2x80x94N(R9)SONH2, xe2x80x94N(R9)SONR8R9, xe2x80x94N(R9)SONH2, xe2x80x94N(R9)SO2NH2, xe2x80x94N(R9)SONR8R9 or xe2x80x94N(R9)Cyc1 [where Cyc1 is an optionally substituted C3-7 monocyclic carbocyclic group optionally containing one or more xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R6)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O2)xe2x80x94 groups].
Cyclic amino substituents which may be present on R3 aliphatic or heteroaliphatic groups include groups of formula xe2x80x94NHet1, where xe2x80x94NHet1 is an optionally substituted C3-7 cyclic amino group optionally containing one or more other heteroatoms or heteroatom containing groups selected from xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R6)xe2x80x94, xe2x80x94C(O), xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O2)xe2x80x94 groups.
Particular examples of amino, substituted amino and cyclic amino groups include xe2x80x94NH2, methylamino, ethylamino, dimethylamino, diethylamino, xe2x80x94NHCyc1 where Cyc1 is an optionally substituted cyclopentyl, cyclohexyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl or thiomorpholinyl group, or xe2x80x94NHet1 where xe2x80x94NHet1 is an optionally substituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl or thiomorpholinyl group. Optional substituents which may be present on these groups and substituted and cyclic amino groups in general include one, two or three halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or C1-4alkyl, e.g. methyl or ethyl, xe2x80x94NH2-, xe2x80x94NHCH3-, xe2x80x94N(CH3)2, hydroxyl, or C1-4alkoxy, e.g. methoxy or ethoxy groups.
When R3 is present in compounds of formula (1) as an optionally substituted cycloaliphatic group it may be an optionally substituted C3-10 cycloaliphatic group. Particular examples include optionally substituted C3-10cycloalkyl, e.g. C3-7cycloalkyl, or C3-10cycloalkenyl e.g. C3-7cycloalkenyl groups.
Heteroaliphatic or heterocycloaliphatic groups represented by R3 include the aliphatic or cycloaliphatic groups just described for R3 but with each group additionally containing one, two, three or four heteroatoms or heteroatom-containing groups represented by X2, where X2 is as described above.
Particular examples of R3 cycloaliphatic and heterocycloaliphatic groups include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclo-penten-1-yl, 2,4-cyclopentadien-1-yl, 3,5,-cyclohexadien-1-yl, tetrahydro-furanyl, pyrroline, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, dioxolanyl, e.g. 1,3-dioxolanyl, imidazolinyl, e.g. 2-imidazolinyl, imidazolidinyl, pyrazolinyl, e.g. 2-pyrazolinyl, pyrazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-trithianyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-, 6H-1,2-, 2H-1,2- or 4H-1,4- oxazinyl, 1,2,5-oxathiazinyl, isoxazinyl, oxathiazinyl, e.g. 1,2,5 or 1,2,6-oxathiazinyl, or 1,3,5-oxadiazinyl groups.
Optional substituents which may be present on R3 cycloaliphatic and heterocycloaliphatic groups include C1-6alkyl groups and those optional substituents described above for R3 when it is an aliphatic group. The heterocycloaliphatic groups may be attached to the remainder of the molecule of formula (1) through any appropriate ring carbon or heteroatom.
When R3 is present as an aromatic or heteroaromatic group in compounds of formula (1) it may be for example an optionally substituted aromatic or heteroaromatic group as described above in relation to the group Ar. Optional substituents which may be present on these aromatic or heteroaromatic groups include one, two or three R4b or -Alk(R4b)m substituents where R4b is an atom or group as described above for R4, and Alk and m are as described previously. Particular substituents include optionally substituted C1-6alkyl groups [wherein the optional substituents include one, two or three of those optional substituents described above for R3 when it is an aliphatic group and halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms or hydroxyl, C1-6alkoxy, e.g. methoxy or ethoxy, thiol, C1-6alkylthio, e.g. methylthio or ethylthio, xe2x80x94SC(NH)NH2, xe2x80x94CH2C(NH)NH2, amino, substituted amino or cyclic amino groups as described above for the optinoal substituents on aliphatic R3 groups.
The presence of certain substituents in the compounds of formula (1) may enable salts of the compounds to be formed. Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isethionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, piperazine, dimethylamine or diethylamine salts.
Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
It will be appreciated that depending on the nature of the group Ar and the substituent R2, the compounds of formula (1) may exist as tautomers and/or geometrical isomers and/or may have one or more chiral centres so that enantiomers or diasteromers may exist. It is to be understood that the invention extends to all such tautomers and isomers of the compounds of formula (1), and to mixtures thereof, including racemates.
In the compounds according to the invention the aromatic group represented by Ar is preferably a substituted phenyl group. The heteroaromatic group represented by Ar is preferably a substituted five- or six-membered monocyclic heteroaromatic group or a nine- or ten-membered fused-ring heteroaromatic group, each of said groups containing one or two oxygen, sulphur and/or nitrogen atoms. Particularly useful groups of these types include substituted pyridyl, indolyl, benzimidazolyl, indazolyl, benzothiazolyl, quinolyl, isoquinolyl and benzoxazolyl groups. Substituted quinolyl, indazolyl or benzothiazolyl groups are especially useful. The substituent(s) present on any of the above-mentioned preferred Ar groups may be any of those xe2x80x94R4 or -Alk(R4)m atoms or groups, particularly one, two or three xe2x80x94R4 and/or -Alk(R4)m atoms or groups, generally or particularly described above and hereinafter in the Examples. Particularly useful substituents are those which contain one or more basic centres, as described hereinafter. In one preference, at least one xe2x80x94R4 or -Alk(R4)m substituent will contain a basic centre.
In general in compounds of the invention R1 is preferably a hydrogen atom.
In one general preference, R2 in compounds of formula (1) is a group xe2x80x94X1R3 in which X1 is a direct bond. In these compounds R3 is preferably an optionally substituted aromatic group or an optionally substituted heteroaromatic group containing one or two ring oxygen, sulphur and/or nitrogen atoms and is especially a monocyclic heteroaromatic group. Thus in particular R3 may be an optionally substituted phenyl, thienyl, thiazolyl, indolyl or pyridyl group. The pyridyl group may in general be attached to the remainder of the compound of formula (1) through any available ring carbon atom and is in relation to that carbon atom, a 2-, 3- or 4-pyridyl group. Substituted 3-pyridyl groups are especially useful. Substituents which may be present on these R3 aromatic and heteroaromatic groups include one, two or three xe2x80x94R4b or -Alk(R4b)m substituents as described in general and in particular above and hereinafter in the Examples. In one preference, at least one xe2x80x94R4b or -Alk(R4b)m substituent will contain a basic centre as described hereinafter.
A particularly useful group of compounds according to the invention has the formula (1) wherein Ar is a substituted phenyl, six-membered monocyclic heteroaromatic group or nine- or ten-membered fused-ring heteroaromatic group, each of said groups containing one or two oxygen, sulphur and/or nitrogen atoms; R1 is a hydrogen atom and R2 is an optionally substituted phenyl, thienyl, thiazolyl or monocyclic or bicyclic heteroaromatic group containing one or two oxygen, sulphur and/or nitrogen atoms.
In compounds of this type, Ar is especially a substituted phenyl, pyridyl, indolyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl or benzoxazolyl group. Substituted phenyl groups are particularly useful. The group R2 is preferably an optionally substituted thienyl, phenyl, indolyl or pyridyl group.
The substituents which may be present on Ar or R2 groups of these types include one, two or three of those xe2x80x94R4, -Alk(R4)m, xe2x80x94R4b and/or -Alk(R4b)m substituents generally and particularly described above in relation to compounds of formula (1), especially substituents which contain one or more basic centres. Particularly useful substituents containing basic centres include nitrogen containing groups such as amino, substituted amino and cyclic amino groups, as described above in relation to optional substituents present on R3 aliphatic groups, optionally substituted and nitrogen-containing heteroaromatic groups, particularly five- or six-membered nitrogen-containing monocyclic heteroaromatic groups such as optionally substituted imidazolyl groups.
Particular groups containing basic centres include xe2x80x94X1a(Alka)pNR7aR7b (where X1a is a direct bond or a linker atom or group as defined above for X1, Alka is as defined above for Alk, p is zero or an integer 1) and R7a and R7b which may be the same or different is each a hydrogen atom or a straight or branched C1-6alkyl group, xe2x80x94X1a(Alka)pNHet1 (where xe2x80x94NHet1 is as defined above) and xe2x80x94X1a(Alka)pAr2 (where Ar2 is a nitrogen containing heteroaromatic group as described above for Ar). In these groups, NR7aR7b may in particular be xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94NHCH2CH3, xe2x80x94N(CH3)(CH2CH3), or xe2x80x94N(CH2CH3)2, xe2x80x94NHet1 may in particular be optionally substituted pyrrolidinyl, piperidinyl, imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl or pyrazolidinyl; Ar2 may in particular be optionally substituted imidazolyl. X1a when present may in particular be an oxygen atom or a xe2x80x94NHxe2x80x94 group.
Especially useful xe2x80x94R4b and -Alk(R4b)m substituents in compounds of the invention include xe2x80x94NH2, xe2x80x94(CH2)2NH2, xe2x80x94C(CH3)2NH2, xe2x80x94C(CH3)2NHCH3, xe2x80x94C(CH3)2N(CH3)2, xe2x80x94CH2N(CH2CH3)2, xe2x80x94CONH(CH2)2N(CH2CH3)2, xe2x80x94C(CH3)2xe2x80x94 pyrrolidinyl, dimethylaminopyrrolidinyl, imidazolyl, imidazolylmethyl, imidazolylethyl and piperidinylethyl groups. Particularly useful xe2x80x94R4 and -Alk(R4)m substituents include fluorine and chlorine atoms and methyl, ethyl, methoxy, xe2x80x94CF3, xe2x80x94CH2F2, xe2x80x94CH2F, xe2x80x94OH, xe2x80x94OCF3, xe2x80x94OCHF3, xe2x80x94OCHF2, xe2x80x94OCH2F, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, Ar2a where Ar2a is imidazolyl, C1-3alkylimidazolyl, triazolyl or C1-3alkyl-triazolyl, xe2x80x94C1-3alkylAr2a, xe2x80x94OC1-3alkylAr2a, xe2x80x94NHet1a, where xe2x80x94NHet1a is piperidinyl, C1-3alkylpiperidinyl, morpholinyl, C1-3alkylmorpholinyl, pyrrolidinyl, C1-3alkylpyrrolidinyl, piperazinyl, C1-3alkylpiperazinyl, imidazolidinyl, C1-3alkylimiazolidinyl, pyrazolidinyl or C1-3alkylpyrazolidinyl, xe2x80x94C1-3alkylNHet1a, xe2x80x94OC1-3alkylNHet1a, and xe2x80x94NHCOAr3where Ar3 is phenyl optionally substituted by Ar2a, xe2x80x94C1-3alkylAr2a, xe2x80x94OC1-3alkylAr2a, xe2x80x94NHet1, xe2x80x94C1-3alkylNHet1 and xe2x80x94OC1-3alkylNHet1.
In the above preferred groups the term triazolyl is intended to mean all possible isomers as described above in relation to the group Ar and especially includes 1,2,3- and 1,2,4-triazolyl groups.
Particularly useful compounds of the invention include:
5-Cyano-4-phenyl-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine;
5-Cyano-N-[4-(2-imidazol-1-ylethyl)phenyl]-4-(4-methoxcarbonylphenyl)pyrimidine-2-amine;
5-Cyano-4-(4-hydroxymethylphenyl)-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine;
5-Cyano-4[(4-N,N-diethylaminomethyl)phenyl]-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine;
5-Cyano-4-[2-(3(R)-dimethylaminopyrrolidin-1-yl)pyridin-5-yl]-N-(indazol-5-yl)pyrimidine-2-amine;
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(indazol-5-yl)pyrimidine-2-amine;
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine;
5-Cyano-N-[4-(2-N,N-diethylaminoethylaminocarboxy)phenyl]-4-phenylpyrimidine-2-amine;
5-Cyano-4-phenyl-N-{4-[2-(2-ethylimidazol-1-yl)ethyl]phenyl}-pyrimidine-2-amine;
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-4(1,2,3-triazol-1-yl)-phenyl]pyrimidine-2-amine;
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-(2-ethylimidazol-1-yl)ethyl]phenyl}pyrimidine-2-amine;
N-[3-(5-Cyano-4-thiophen-2-ylpyrimidin-2-ylamino)phenyl]-4-(4-methylpiperazin-1-ylmethyl)benzamide;
4-[3-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-(2-methylimidazol-1-yl)ethyl]phenyl}pyrimidine-2-amino;
5-Cyano-4-[4-(imiadzol-1-yl)methyl]phenyl-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amino;
and the salts, solvates, hydrates and N-oxides thereof.
Especially useful compounds according to the invention include:
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4(1,2,4-triazol-1-yl)phenyl]pyrimidine-2-amine;
5-Cyano-N-[4-(1,2,4-triazol-1-yl)phenyl]-4-[4-(1-dimethylamino-1-methylethyl)phenyl]pyrimidine-2-amine;
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(4-fluorophenyl)pyrimidine-2-amine;
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-piperidin-1-ylethyl]phenyl}pyrimidine-2-amine;
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-imidazol-1-ylethyl)phenyl]pyrimidine-2-amine;
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-morpholinoethyl)phenyl]pyrimidine-2-amine;
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[3-(2-morpholinoethyl)phenyl]pyrimidine-2-amine;
5-Cyano-4-[4-(1-methyl-1-pyrrolidin-1-ylethyl)phenyl]-N-(4-fluorophenyl)pyrimidine-2-amine;
5-Cyano-4-{2-([2-(diethylamino)ethyl]amino)pyridin-5-yl}-N-(4-fluorophenyl)pyrimidine-2-amine;
4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3-fluorophenyl)pyrimidine-2-amine;
and the salts, solvates, hydrates and N-oxides thereof.
Compounds according to the invention are potent and selective inhibitors of KDR and/or FGFr kinases as demonstrated by differential inhibition of these enzymes when compared to inhibition of other protein kinases such as EGFr kinase, p56lck kinase, ZAP-70 kinase, protein kinase C, Csk kinase and p59fyn kinase. The ability of the compounds to act in this way may be simply determined by employing tests such as those described in the Examples hereinafter.
The compounds according to the invention are thus of particular use in the prophylaxis and treatment of diseases in which inappropriate KDR kinase action plays a role, for example in disease states associated with angiogenesis. The compounds are then of use for example in the prophylaxis and treatment of cancer, prosiasis, rheumatoid arthritis, Kaposi""s Sarcoma, ischemic heart disease, atherosclerosis and occular diseases, such as diabetic retinopathy, involving retinal vessl proliferation and the invention is to be understood to extend to such uses and to the use of a compound of formula (1) in the preparation of a medicament for the prophylaxis and treatment of such diseases.
For the prophylaxis or treatment of disease the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds for formula (1) may be formulated for parenteral administration by injection, including bolus injection or infusion or particle mediated injection. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials or a device containing a compressed gas such as helium for particle mediated administration. The compositions for bolus injection or infusion may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. For particle mediated administration the complex may be coated on particles such as microscopic gold particles.
In addition to the formulations described above, the compounds of formula (1) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection. Where desired, the compounds according to the invention may also be conjugated to a polymer, e.g. a naturally occuring polymer such as albumin, to prolong the half life of the compounds when in use. Such conjugates may be formulated and delivered as described above.
For nasal administration or administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
The quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, daily dosages may range from around 100 ng/kg to 100 mg/kg e.g. around 0.01 mg/kg to 40 mg/kg body weight for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration and around 0.05 mg to around 1000 mg e.g. around 0.5 mg to around 1000 mg for nasal administration or administration by inhalation or insufflation.
The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process description, the symbols R1, R2, Alk, Alk1 and Ar when used in the text or formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, (1991)]. In some instances, deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups.
Thus according to a further aspect of the invention, a compound of formula (1) may be prepared by reaction of a guanidine of formula (2):
xe2x80x83Arxe2x80x94N(R1)C(xe2x95x90NH)NH2xe2x80x83xe2x80x83(2)
or a salt thereof
with an enaminone of formula (3):
R2COC(CN)CHN(R10)(R11)xe2x80x83xe2x80x83(3)
where R10 and R11, which may be the same or different is each a C1-6 alkyl group.
The reaction may be performed in a solvent, for example a protic solvent such as an alcohol, e.g. ethanol, methoxyethanol or propan-2-ol, optionally in the presence of a base e.g. an alkali metal base, such as sodium hydroxide or potassium carbonate, at an elevated temperature, e.g. the reflux temperature.
Salts of the compounds of formula (2) include acid salts such as inorganic acid salts e.g. hydrochlorides or nitrates.
Intermediate guanidines of formula (2) may be prepared by reaction of the corresponding amine ArNH2 with cyanamide at an elevated temperature. The reaction may be performed in a solvent such as ethanol at an elevated temperature, e.g. up to the reflux temperature. Where it is desired to obtain a salt of a guanidine of formula (2), the reaction may be performed in the presence of a concentrated acid, e.g. hydrochloric or nitric acid.
The amines ArNH2 are either known compounds or may be obtained by conventional procedures, for example by hydrogenation of the corresponding nitro derivatives using for example hydrogen in the presence of a metal catalyst in a suitable solvent, for example as more particularly described in the interconversion reactions discussed below. The nitrobenzenes for this particular reaction are either known compounds or may be prepared using similar methods to those used for the preparation of the known compounds.
Intermediate enaminones of formula (3) are either known compounds or may be prepared by reaction of an acetyl derivative R2COCH2CN with an acetal (R10)(R11)NCH(OR12)2 (where R12 is a C1-6alkyl group such as a methyl or ethyl group) at an elevated temperature. The starting materials for this reaction are either known compounds or may be prepared by methods analogous to those used for the preparation of the known compounds.
One particularly useful method for the preparation of acetyl derivatives R2COCH2CN involves treating a corresponding isoxazole of formula (4): 
with a base such as an alkoxide, e.g. sodium ethoxide, in a solvent such as an alcohol, e.g. ethanol, at ambient temperature. Intermediate isoxazoles of formula (4) may be obtained by reaction of the corresponding aminopropenone (R2COCHCHN(R10)(R11) with hydroxyl-amine in a solvent such as an alcohol, e.g. MeOH at ambient temperature. The aminopropenone starting material for this rection may be obtained by reaction of the corresponding methyl ketone R2COCH3 with an acetal (R10)(R11)NCH(OR12)2 as described above.
In another process according to the invention, a compound of formula (1) may be prepared by displacement of a chlorine atom in a pyrimidine of formula (5): 
with an amine ArNH2.
The reaction may be performed at an elevated temperature, for example the reflux temperature, where necessary in the presence of a solvent, for example an alcohol, such as 2-ethoxyethanol or isopopanol, a cyclic ether, e.g. dioxane or a substituted amide such as dimethylformamide, optionally in the presence of a base, for example an organic amine such as pyridine.
Intermediate pyrimidines of formula (5) may be obtained by reaction of a corresponding pyrimidine of formula (6): 
with phosphorous oxychloride optionally in a solvent such as a substituted amide e.g. dimethylformamide at an elevated temperature, for example the reflux temperature.
Intermediates of formula (6) may be prepared from the corresponding amine of formula (7): 
with sodium nitrite in an aqueous acid, e.g. aqueous sulphuric acid at around ambient temperature.
Amines of formula (7) may be prepared by reaction of an enaminone of formula (3) with a guanidine salt, e.g. guanidine carbonate, as described above for the preparation of compounds of formula (1).
Compounds of formula (1) may also be prepared by interconversion of other compounds of formula (1) and it is to be understood that the invention extends to such interconversion processes. Thus, for example, standard substitution approaches employing for example alkylation, arylation, heteroarylation, acylation, thioacylation, sulphonylation, formylation or coupling reactions may be used to add new substitutents to and/or extend existing substituents in compounds of formula (1). Alternatively existing substituents in compounds of formula (1) may be modified by for example oxidation, reduction or cleavage reactions to yield other compounds of formula (1).
The following describes in general terms a number of approaches which can be employed to modify existing Ar and/or R2 groups in compounds of formula (1). It will be appreciated that each of these reactions will only be possible where an appropriate functional group exists in a compound of formula (1).
Where desired, these reactions may also be performed on intermediates to compounds of formula (1), for example in the preparation of intermediate amines, ArNH2 or acetyl derivatives R2COCH2CN, and the description which follows is intended to apply to these intermediates even though only a compound of formula (1) is mentioned.
Thus, for example alkylation, arylation or heteroarylation of a compound of formula (1) may be achieved by reaction of the compound with a reagent AlkL or Ar3L, where Alk is an alkyl group and Ar3 is an aryl or heteroaryl group as defined above in relation to compounds of formula (1) and L is a leaving atom or group such as a halogen atom, e.g. a chlorine or bromine atom, or a sulphonyloxy group, e.g. an arylsulphonyloxy group such as a p-toluenesulphonyloxy group.
The alkylation, arylation or heteroarylation reaction may be carried out in the presence of a base, e.g. an inorganic base such as a carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride, in a dipolar aprotic solvent such as an amide, e.g. a substituted amide such as dimethylformamide or an ether, e.g. a cyclic ether such as tetrahydrofuran, at around 0xc2x0 C. to around 40xc2x0 C.
In a variation of this process the leaving group L may be alternatively part of the compound of formula (1) and the reaction performed with an appropriate nucleophilic reagent at an elevated temperature. Particular nucleophilic reagents include cyclic amines, such as piperazine or imidazole. Where appropriate the reaction may be performed in a solvent such as an aprotic solvent, e.g. a substituted amide such as dimethylformamide.
In another general example of an interconversion process, a compound of formula (1) may be acylated orthioacylated. The reaction may be performed for example with an acyl halide or anhydride in the presence of a base, such as a tertiary amine e.g. triethylamine in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane or chloroform at for example ambient temperature, or by reaction with a thioester in an inert solvent such as tetrahydrofuran at a low temperature such as around 0xc2x0 C. Alternatively, the reacton may be performed with an acid, in the presence of a condensing agent, for example a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, advantageously in the presence of a catalyst such as a N-hydroxy compound, e.g. a N-hydroxytriazole such as 1-hydroxybenzotriazole in the presence of a base, e.g. a cyclic amine such as N-methylmorpholine. The reaction is particularly suitable for use with compounds of formula (1) containing primary or secondary amino groups.
In a further general example of an interconversion process, a compound of formula (1) may be formylated, for example by reaction of the compound with a mixed anhydride HCOOCOCH3 or with a mixture of formic acid and acetic anhydride.
Compounds of formula (1) may be prepared in another general interconversion reaction by sulphonylation, for example by reaction of the compound with a reagent AlkS(O)2L, or Ar2S(O)2L in the presence of a base, for example an inorganic base such as sodium hydride in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide at for example ambient temperature. The reaction may in particular be performed with compounds of formula (1) possessing a primary or secondary amino group.
In further examples of interconversion reactions according to the invention compounds of formula (1) may be prepared from other compounds of formula (1) by modification of existing functional groups in the latter.
Thus in one example, ester groups xe2x80x94CO2Alk1 in compounds of formula (1) may be converted to the corresponding acid [xe2x80x94CO2H] by acid- or base-catalysed hydrolysis or by catalytic hydrogenation depending on the nature of the group Alk1. Acid- or base-catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e.g. TFA acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol or ether e.g. aqueous MeOH or tetrahydrofuran. Catalytic hydrogenation may be carried out using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol, e.g. MeOH.
In a second example, xe2x80x94OAlk2 [where Alk2 represents an alkyl group such as a methyl group] groups in compounds of formula (1) may be cleaved to the corresponding alcohol xe2x80x94OH by reaction with boron tribromide in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at a low temperature, e.g. around xe2x88x9278xc2x0 C.
In another example, alcohol xe2x80x94OH groups in compounds of formula (1) may be converted to a corresponding xe2x80x94OAlk or xe2x80x94OAr group by coupling with a reagent AlkOH or ArOH in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
Aminosulphonylamino [xe2x80x94NHSO2NH2] groups in compounds of formula (1) may be obtained, in another example, by reaction of a corresponding amine [xe2x80x94NH2] with sulphamide in the presence of an organic base such as pyridine at an elevated temperature, e.g. the reflux temperature.
In another example of an interconversion process secondary amine groups in compounds of formula (1) may be alkylated using an alcohol, e.g. ethanol and catalytic hydrogenation, employing for example hydrogen in the presence of a metal catalyst such as palladium on a support such as carbon.
In a further example, amine [xe2x80x94NH2] groups in compounds of formula (1) may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature. In an alternative, amine groups may also be generated by reduction of the corresponding nitrile, for example using a reducing agent such as a borohydride, e.g. sodium borohydride or cerium trichloride. Alternatively, amine groups may be obtained by CeIV oxidation of the corresponding p-anisyl- or p-anisylmethylamines using for example ceric ammonium nitrate in a solvent such as acetonitrile.
In another example cyclic amino groups in compounds of formula (1) may be prepared by cyclisation of a corresponding compound containing an amine [xe2x80x94NH2] group with a reagent L1AlkL2 where L1 and L2 which may be the same or different is each a leaving atom or group as described above L and may for example each be a halogen atom such as a bromine atom. The reaction may advantageously be carried out in the presence of a base e.g. an inorganic base such as potassium carbonate, at an elevated temperature.
In another example, a nitro [xe2x80x94NO2] group may be reduced to an amine [xe2x80x94NH2], for example by catalytic hydrogenation as just described, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
N-oxides of compounds of formula (1) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70xc2x0 C. to 80xc2x0 C., or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
Where salts of compounds of formula (1) are desired, these may be prepared by conventional means, for example by reaction of a compound of formula (1) with an appropriate acid or base in a suitable solvent or mixture of solvents, e.g. an organic solvent such as an ether, e.g. diethylether, or an alcohol, e.g. ethanol.
The following Examples illustrate the invention. In the Examples all 1Hnmr were run at 300 MHz unless specified otherwise. All temperatures are in xc2x0 C.
The following abbreviations are used:
THFxe2x80x94tetrahydrofuran;
DMSOxe2x80x94dimethylsulphoxide;
DIBAL-Hxe2x80x94diisobutylaluminium hydride;
DMFxe2x80x94dimethylformamide;
TFAxe2x80x94trifluoroacetic acid;
MeOHxe2x80x94methanol.
The title compound was prepared from 4-[2-(1,2,3-triazol-1-yl)ethoxy]aniline (4.91 g, 24.07 mmol), cyanamide (1.56 g, 40.97 mmol) and concentrated HNO3 (1.58 mL, 26.47 mmol) in a manner similar to the guanidine of Example 1 to give the desired material (4.7 g) as an off-white solid, m.p. greater than 250xc2x0. xcex4H (d6DMSO) 9.33 (1H, s), 8.20 (1H, s), 7.74 (1H, s), 7.17-7.14 (6H, m), 7.00-6.97 (2H, m), 4.79 (2H, t, J 4.95 Hz) and 4.41 (2H, t, J 4.95 Hz).
4-[2-(1,2,3-Triazol-1-yl)ethoxy]aniline was prepared from 4-[2-(1,2,3-triazol-1-yl)ethoxy]nitrobenzene (5.98 g, 25.5 mmol) and 10% palladium on charcoal (1.5 g) in a manner similar to the aniline intermediate of Example 12 to give the desired material (4.91 g) as a yellow solid m.p. 141xc2x0. xcex4H (CDCl3) 7.69 (1H, d, J 0.5 Hz), 7.62 (1H, d J 0.5 Hz), 6.65 (2H, d, J 5.8 Hz), 6.58 (2H, d, J 5.8 Hz), 4.71 (2H, t, J 5.0 Hz), 4.24 (2H, t, J 5.0 Hz) and 3.43 (2H, s).
4-[2-(1,2,3-Triazol-1-yl)ethoxy]nitrobenzene was prepared from 4-[(2-p-toluenesulphonyloxy)ethoxy]nitrobenzene (10 g, 29.7 mmol) and 1,2,3-triazole, sodium salt (2.46 mmol) in a manner similar to the analogous reaction of Example 24 to give the desired material (2.25 g) as yellow solid, m.p. 123xc2x0. xcex4H (d6DMSO) 8.21 (1H, s), 8.20 (2H, d, J 2.3 Hz), 7.74 (1H, d, J 0.5 Hz), 7.14 (2H, d, J 2.4 Hz), 4.84 (2H, t, J 4.9 Hz) and 4.57 (2H, t, J 4.9 Hz). The reaction also yielded 4-[2-(1,2,3-triazol-2-yl)ethoxy]nitro-benzene (4.36 g) as a yellow solid, m.p. 111xc2x0. xcex4H (d6DMSO) 8.17 (2H, d, J 9.3 Hz), 7.80 (2H, s), 7.11 (2H, d, J 9.3 Hz), 4.86 (2H, t, J 4.8 Hz) and 4.64 (2H, t, J 4.8 Hz).
The title compound was prepared from 4-[2-(1,2,3-triazol-2-yl)ethoxy]aniline (8.85 g, 43.4 mmol), cyanamide (2.82 g, 73.78 mmol) and concentrated HNO3 (1.58 mL, 26.47 mmol) in a manner similar to the guanidine of Example 1 to give the desired material (7.95 g) as an off-white solid, m.p. greater than 250xc2x0. xcex4H (d6DMSO) 9.32 (1H, s), 7.80 (2H, s), 7.16-7.13 (6H, m), 7.00-6.97 (2H, m), 4.79 (2H, t, J 4.95 mmol) and 4.41 (2H, t, J 4.95 mmol).
4-[2-(1,2,3-Triazol-2-yl)ethoxy]aniline was prepared from 4-[2-(1,2,3-triazol-2-yl)ethoxy]nitrobenzene (10.5 g, 44.8 mmol) and 10% palladium on charcoal (1.5 g) in a manner similar to the aniline intermediate of Example 12 to give the desired material (4.91 g) as a yellow solid m.p. 159xc2x0. xcex4H (CDCl3) 7.62 (2H, s), 6.73-6.58 (4H, m), 4.77 (2H, t, J 5.8 Hz), 4.40 (2H, t, J 5.8 Hz) 3.43 (2H, s).
The title compound was prepared from 4-[2-(1,2,4-triazol-1-yl)ethoxy]aniline (5.30 g, 25.9 mmol), cyanamide (1.86 g, 44.11 mmol) and concentrated HNO3 (1.88 mL, 28.54 mmol) in a manner similar to the guanidine of Example 1 to give the desired material (6.62 g) as an off-white solid, m.p. 280-282xc2x0. xcex4H (d6DMSO) 9.33 (1H, bs), 8.56 (1H, s), 7.97 (1H, s), 7.17 (4H, bs), 7.16-7.12 (2H, s), 6.98-6.94 (2H, m), 4.58 (2H, t, J 5.0 Hz) and 4.34 (2H, t, J 2.0 Hz).
4-[12-(1,2,4-Triazol-1-yl)ethoxy]aniline was prepared from 4-[2-(1,2,4-triazol-1-yl)ethoxy]nitrobenzene (6.28 g, 26.8 mmol) and 10% palladium on charcoal (0.5 g) in a manner similar to the aniline intermediate of Example 12 to give the desired material (5.31 g) as a yellow solid m.p. 85-86xc2x0. xcex4H (CDCl3) 8.21 (1H, s), 7.94 (1H, s), 6.69-6.58 (4H, m), 4.51 (2H, t, J 5.0 Hz), 4.24 (2H, 5.2 Hz) and 3.45 (2H, bs).
4-[2-(1,2,4-Triazol-1-yl)ethoxy]nitrobenzene was prepared from 4-[(2-p-toluenesulphonyloxy)ethoxy]nitrobenzene (10 g, 30.7 mmol) and 1,2,4-triazole, sodium salt (3.36 g, 36.8 mmol) in a manner similar to the analogous reaction of Example 24 to give the desired material (6.45 g) as yellow solid, m.p. 118-120xc2x0. xcex4H (CDCl3) 8.21-8.17 (3H, m), 7.97 (1H, s), 6.93-6.90 (2H, m), 4.62 (2H, t, J 5.2 Hz) and 4.45 (2H, t, J 5.3 Hz).
2-Hydroxy-2-pyridin-3-ylacrylonitrile, sodium salt (1.0 g, 5.95 mmol) was dissolved in methanol (20 mL) and dimethylformamide diethylacetal (1.2 mL, 7.0 mmol) followed by 1M hydrochloric acid in diethyl ether (5.95 mL) were added. The reaction was stirred at room temperature for 1.5 h and then concentrated under reduced pressure. The resulting residue was subjected to column chromatography (silica 3% methanol in dichloromethane) to give the desired product (560 mg) as yellow solid. xcex4H (CDCl3) 8.98 (1H, dd, J 2.3, 0.8 Hz), 8.69 (1H, dd, 4.8, 1.6 Hz), 8.08 (1H, dt, J 7.9, 2.2 Hz), 7.98 (1H, s), 7.37-7.33 (1H, m), 3.50 (3H, s) and (3H, s).
2-Hydroxy-2-pyridin-3-ylacrylonitrile was prepared by adding a solution of ethyl nicotinate (22.67 g, 0.15 mol) and acetonitrile (15.6 mol, 0.3 mol) in toluene (100 mL) and DMF (25 mL) to a suspension of sodium ethoxide (9.70 g, 0.143 mol) and the resulting mixture heated at reflux for 2 h with vigorous stirring. On cooling the reaction was diluted with ether (400 mL) and the resulting precipitate collected and washed further with ether to give the desired material (20.1 g) which was used without purification.